2-phenoxyalkanoic acid esters

ABSTRACT

This invention concerns 2-phenoxyalkanoic acid esters which are pharmacologically active as anticholesterol agents.

United States Patent [191 Grant et al.

[ 51 Feb. 20, 1973 [54] Z-PHENOXYALKANOIC ACID ESTERS [75] Inventors:Norman H. Grant, Wynnewood; Harvey E. Alburn, West Chester, both of Pa.

[73] Assignee: American Home Products Corporation, New York, NY.

[22] Filed: June 18, 1968 [21] Appl. No.: 737,837

[52] US. Cl...- ..260/473 G, 260/326 R, 260/3263,

. 260/326 HL, 424/308 [51] Int. Cl ..C07c 69/76 [58] Field of Search..260/473 G [56] References Cited UNITED STATES PATENTS 3,494,957 2/1970Nakanishi ..260/473 3,448,] 10 6/1969 Groit ..260/294.3 2,759,965 8/1956Begin ..260/473 2,396,513 3/1946 Jones ..167/45 FOREIGN PATENTS ORAPPLICATIONS [5 7] ABSTRACT This invention concerns 2-phenoxyalkanoicacid esters which are pharmacologically active as anticholesterolagents.

7 Claims, No Drawings Z-PHENOXYALKANOIC ACID ESTERS ilt...

wherein R, is selected from the group consisting of hydrogen, halogen,lower alkyl and lower alkoxy; R, and R are selected from the groupconsisting of hydrogen and lower alkyl; and R is selected from the groupconsisting of lower alkoxy(lower)alkyl, succinimido and phthalimido. Asemployed herein the terms lower alkyl, lower alkoxy and the like aremeant to include both branched and straight chain moieties containingfrom one to about eight carbon atoms. Typical examples of the compoundsof this invention are: 2-(p-chlorophenoxy)-2-methylpropionic acid,methoxymethyl ester; 2-(p-chlorophenoxy)-2- methylpropionic acid,succinimido ester; 2(pbromophenoxy)-2-methylpropionic acid, succinimidoester; and Z-(p-chlorophenoxy)-2-methylpropionic acid, phthalimidoester.

' The new and novel 2-phenoxya'lkanoic acid, alkoxyalkyl esters of thepresent invention may be prepared by the process which is hereinafterschematically illustrated:

wherein R R and R are defined as above and X is halogen and R is loweralkoxy(lower)alkyl. The reaction is effected by admixing an appropriate2-phenoxyalkanoic acid (I) with a haloalkyl alkylether (II), in thepresence of a basic catalyst e.g. triethylamine, in ethyl acetate atabout room temperature for a period of about I to about hours.

When the reaction is complete, the resulting 2- phenoxyalkanoic acidalkoxyalkyl ester (III) is separated by conventional procedures. Forexample, the reaction mixture is filtered, washed with water andconcentrated.

The new and novel succinimido and phthalimido esters of theseZ-phenoxyalkanoic acids may be prepared by the process which is depictedas follows:

R2 Q-O-i-C 0 0H HORQ wherein R R and R are defined as above and R issuccinimido or phthalimido. The reaction is effected by admixing anappropriate Z-phenoxyalkanoic acid (I) with a basic catalyst e.g.triethylamine, in a reactioninert organic solvent at a temperature belowabout 0C. An alkylhalocarbonate e.g. ethylchloroformate is then added tothis mixture, the temperature is allowed to equilibrate to about roomtemperature and the mixture is diluted with ethyl ether. Thereafter, aN-hydroxy succinimide or phthalimide (IV) is added to the reactionmixture with stirring.

When the reaction is complete, the resulting 2- phenoxyalkanoic acidsuccinimido or phthalimido ester (V) is separated by conventionalprocedures. For example, the reaction mixture is extracted with anaqueous bicarbonate solution, water and then concentrated to afford theproduct (V) which can be recrystallized from a suitable solvent e.g.ethyl ether.

The Z-phenoxyalkanoic acid (I) starting materials employed in the abovereactions may be prepared by procedures known in the art, for example,the process described by Galimberti, P. and Defranceschi, A. in Gazz.Chim. Ital, 77, 431 (1947) as exemplified in hereinafter Example I. Theother reactants e.g. the haloalkyl alkylethers (II) and N-hydroxysuccinimide or phthalimide (IV) employed in the above process arecommercially available and/or may be prepared by well known chemicalprocedures. In the above reaction, by the term reaction-inert organic"solvent is meant any organic solvent that will dissolve the reactantsand not interfere with their interaction. Many such solvents willreadily suggest themselves to those skilled in the art, e.g. ethylacetate, chloroform, acetonitrile, dioxan and the like.

The new and novel 2-phenoxyalkanoic acid esters (III) and (V) of thepresent invention possess valuable pharmacological activity. Inparticular, these compounds in standard pharmacological proceduresdemonstrate an ability to reduce serum cholesterol and are useful asanticholesterol agents.

In the pharmacological evaluation of the cholesterol lowering propertiesof the compounds of this invention the in vivo effects of the compoundsare tested as follows:

Male weanling rats are fed a hypercyolesterolemic diet for 3 weeks.Serum cholesterol is determined on 0.01 ml of serum separated from tailblood collected in a capillary tube. Groups of rats with equal averageserum cholesterol are given the test compound orally once a day bysyringe for 3 days. Serum cholesterol is determined in the morning ofthe fourth day. Anticholesterol activity is demonstrated by a loweringof the serum cholesterol.

The 2-phenoxyalkanoic acid alkoxyalkyl esters (III), the2-phenoxyalkanoic acid succinimido esters (V) and the 2-phenoxyalkanoicacid phthalimido esters (V) of this invention in the above testprocedure when administered orally at a daily dosage of about 30 toabout 50 mg./rat. of animal body weight lower the serum cholesterollevel in hypercholesterolemic rats by about 45 to about percent in 3days.

When the compounds of this invention are employed as serum cholesterollowering agents they may be administered to warm-blooded animals, e.g.,mice, rats, rabbits, dogs, cats, monkeys, etc. alone or in combinationwith pharmacologically acceptable carriers, the proportion of which isdetermined by the solubility and chemical nature of the compounds,chosen route of administration and standard biological practice. Forexample, they may be administered orally in the form containing suchexcipients as starch, milk sugar, and so forth. They may also beadministered orally in the form of solutions or they may be injectedparenterally. For parenteral administration they may be used in the formof a sterile solution containing other solutes, for example, enoughsaline or glucose to make the solution isotonic.

The dosage of the present anticholesterol agents will vary with the formof administration and the particular compound chosen. Furthermore, itwill vary with the particular subject under treatment. Generally,treatment is initiated with small dosages substantially less than theoptimum dose of the compound. Thereafter, the dosage is increased bysmall increments until the optimum effect under the circumstances isreached. In general, the compounds of this invention are most desirablyadministered at a concentration level that will generally affordeffective results without causing any harmful or deleterious sideeffects and preferably at a level that is in the range of from about 40mg. to about 400 mg. per kilo per day, although as mentioned abovevariations will occur.

The following examples are given by way of illustration and are not tobe construed as limitations of this invention, many variations of whichare possible without departing from the scope and spirit thereof.

EXAMPLE I To 40.0 g. of p-chlorophenol (0.312 moles) dissolved in 382ml. of acetone (300 g.), there is slowly added 70.0 g. of solid sodiumhydroxide and 33.6 ml. of chloroform (50 g.). The resulting mixture isrefluxed for 4'hours and then evaporated until a viscous brown liquidbegins to solidify. This solid is redissolved in 300 ml. of water withheating, then acidified to about pH 2.0 with concentrated hydrochloricacid (40 ml.). The resulting brown precipitate is filtered, washed withwater, dissolved in 600 ml. of 7% sodium bicarbonate, extracted withether, treated with charcoal, filtered, washed with water and acidifiedto pH 4.0 with concentrated hydrochloric acid. The resulting solid isfiltered, recrystallized from 500 ml. of a 7% sodium bicarbonatesolution to afford 2-(p-chlorophenoxy)-2-methylpropionic acid, m.p. 119C.

Anal. Calcd for C H O Cl: C, 56.12; H, 5.18; O, 22.43;Cl, 16.57.

Found: C, 55.98; H, 4.94; Cl, 16.77.

EXAMPLE ll To a solution of 12.0 g. of 2-(p-chlorophenoxy)-2-methylpropionic acid in 600 ml. of ethylacetate there is added 4.5 g. ofchloromethyl methylether, followed by 7.74 ml. of triethylamine. Themixture is stirred at room temperature for one hour and then allowed tostand overnight. The system is filtered, washed with water, and thenconcentrated to the oily product which weighs 13.4 g. and is2-(p-chlorophenoxy-Z-niethylpropionic acid, methoxymethyl ester.

Anal. Calc'd for C H CIO C, 55.70; H, 5.80; Cl, 13.72.

Found: C, 55.54; H, 5.86; Cl, 13.43.

In a similar manner, 2-(p-bromophenoxy)propionic acid and chloromethylethyl ester are reacted to yield 2-(p-bromophenoxy)propionic acid,ethoxymethyl ester.

EXAMPLE III acid,

acid, pentoxymethyl EXAMPLE IV A solution of 10.73 g. of2-(p-chlorophenoxy)-2- methylpropionic acid and 7 ml. of triethylaminein 50 ml. of methylene chloride is chilled to 0C. There is then added 5ml. of ethylchloroformate, and the system is stirred and warmed to roomtemperature. After 1 hour there is added 50 ml. of ethyl ether, and thesystem is filtered. The filtrate is adjusted to ml. by addition of ethylether and half of this is then stirred with 2 g. of N-hydroxysuccinimideat room temperature. The mixture is extracted three times with 100 ml.portions of 0.1 M K HPO and then with 10 ml. of water. The ether layeris evaporated to an oil, which solidifies overnight. This product isrecrystallized from ethyl ether, giving 2.0 g. of 2-(p-chlorophenoxy-2-methylpropionic acid, succinimido ester.

Anal. Calcd for C H CINO C, 53.9; H, 4.49; N, 4.49.

Found: C, 53.8; H, 4.44; N, 4.25.

In a similar manner, 2-(p-bromophenoxy)Q-methylpropionic acid is reactedwith N-hydroxysuccinimide to yield 2-(p-bromophenoxy)-2-methylpropionicacid, succinimido ester.

EXAMPLE V A solution of 5.3 g. of 2-(p-chlorophenoxy)-2- methylpropionicacid and 3.5 ml. of triethylamine in 25 ml. of methylene chloride ischilled to 0C. There is then added 2.5 ml. of ethylchloroformate, andthe system is stirred and warmed to room temperature. After 2 hoursthere is added 25 m1. of ethyl-ether, and the system is filtered. Thefiltrate is adjusted to 50 ml.

acid,

by addition of ethyl ether and half of this is then stirred with 1.0 g.of N-hydroxyphthalimide at room temperature. The mixture is extractedthree times with 50 ml. portions of 0.1 M K l-lPO and then with ml. ofwater. The ether layer is evaporated and the residue recrystallized fromethyl ether, giving 2-(pchlorophenoxy)-2-methylpropionic acid,phthalirnido ester.

EXAMPLE VI When the procedure of Examples IV V is repeated to react anappropriate 2-phenoxyalkanoic acid with N- hydroxysuccinimide orN-hydroxyphthalimide the following compounds are obtained: I

2-(o-chlorophenoxy)-2methylpropionic acid, succinimido ester;

2-(p-iodophenoxy)-2-methylpropionic acid, phthalirnido ester;

Z-(p-ethylphenoxy )-2-methylvaleric acid, sucacid, phthalirnido acid,

those having the formula methyl, ethyl and propyl; R is selected fromthe class consisting of methyl, ethyl, propyl and butyl and R is loweralkoxy (lower) alkyl.

2. A compound as described in claim 17 which is: 2-(p-chlorophenoxy)-2-methylpropionic acid, methoxymethyl ester.

3. A compound as described in claim 1, which is: 2-(p-methoxyphenoxy)-2-methylbutyric acid, methoxyethyl ester.

4. A compound as described in claim 1 which is: 2-ethyl-2-(m-propoxyphenoxy)valeric acid, propoxymethyl ester.

5. A compound as described in claim 1 which is: 2-methyl-Z-(p-toloxy)propionic acid, methoxybutyl ester.

6. A compound according to claim 1 wherein R is halogen.

7. A compound according to claim 6 wherein said halogen is in the paraposition.

gg UNITED STATES PATENT OFFICE QERTIFICATE 0F CORRECTKON Patent No.3,717,669 Dated February 20, 1973 Invent (s) Norman H. Grant and Ha vevE, Alburn It is certified that, error appears in the. above-identifiedpatent and that said Letters Patent are hereby corrected as shown below:

Claim 2, line 1 (column 6), change "17" to --l-.

Signed and sealed this 20th day of November 1973.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. RENE D. TEGTMEYER Attesting Officer ActingCommissioner of Patents

1. A compound selected from the group consisting of those having theformula
 2. A compound as described in claim 17 which is:2-(p-chlorophenoxy)-2-methylpropionic acid, methoxymethyl ester.
 3. Acompound as described in claim 1, which is:2-(p-methoxyphenoxy)-2-methylbutyric acid, methoxyethyl ester.
 4. Acompound as described in claim 1 which is:2-ethyl-2-(m-propoxyphenoxy)valeric acid, propoxymethyl ester.
 5. Acompound as described in claim 1 which is:2-methyl-2-(p-toloxy)propionic acid, methoxybutyl ester.
 6. A compoundaccording to claim 1 wherein R1 is halogen.